Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder that is characterized by disturbances in movement, cognition and personality. HD is autosomal dominant. Neurodegeneration is associated with selective neuronal cell death, occurring primarily in the cortex and striatum of the brain.
The mutation that causes HD is an expansion of CAG repeats in the first exon of gene IT-15, that encodes the huntingtin protein (Huntington's Disease Collaborative Research Group, Cell 72:971-83 (1993); Ambrose et al., Somat. Cell Mol. Genet. 20:27-38 (1994)). CAG encodes the amino acid glutamine (“Gln” or “Q”), so CAG repeats encode polyglutamine (or “polyQ”) regions within huntingtin. The polyglutamine region of huntingtin from non-HD individuals contains about 8-31 consecutive Gln residues. Huntingtin with over 37 consecutive Gln residues is associated with mild to severe HD, with the more severe cases exhibiting a polyglutamine region of up to about 68, or more, Gln residues. The same mutational mechanism, expansion of CAG repeats, is responsible for a growing number of less common neurodegenerative disorders that include the spinocerebellar ataxias (SCAs) (Zoghbi et al., Ann. Rev. Neurosci. 23:217-47 (2000)).
Parkinson's disease (PD) is a major neurodegenerative disorder characterized by muscle rigidity, bradykinesia, resting tremor and postural instability (Goedert, Nat. Rev. Neurosci. 2:492-501 (2001)). Although the vast majority of cases of PD are idiopathic, a small percentage of cases are caused by missense mutations in the α-synuclein gene (Polymeropoulos et al., Science 276:2045-47 (1997); Kruger et at., Nat. Genet. 18:106-08 (1998)). One neuropathological feature shared by both HD and PD is the occurrence of ubiquitinated inter-neuronal inclusion bodies in diseased brains. Huntingtin, and/or degradation products of huntingtin, are the major components of cytoplasmic and nuclear inclusion bodies that are observed in HD. α-Synuclein is the major component of inclusion bodies (called Lewy bodies) in PD.
Huntingtin and α-synuclein assemble into fibrillar protein aggregates that display many properties of amyloid in vitro and in vivo (Scherzinger et al., Cell 90:549-58 (1997); Rochet et al., Curr. Opin. Struct. Biol. 10:60-88 (2000)). The “amyloid hypothesis,” developed originally to describe the role of β-amyloid in Alzheimer's Disease (AD), suggests that the aggregation of proteins into an ordered fibrillar structure is causally related to aberrant protein interactions that culminate in neuronal dysfunction and cell death (Hardy et al., Science 297:353-56 (2002)). The similar physical, biochemical, and morphological features of huntingtin, α-synuclein, and other amyloid-forming proteins have led to the speculation that neurodegeneration associated with protein misfolding may have common molecular mechanisms. However, the precise roles of protein aggregation, amyloid formation and inclusion bodies in HD, PD, and other amyloidogenic diseases remain controversial. While significant efforts have been made to understand the roles of huntingtin and α-synuclein in HD and PD, respectively, a unifying pathogenic mechanism has not been identified. Different genes and pathways have been suggested to play important roles in HD and PD (see, e.g., Goedert, Nat. Rev. Neurosci. 2:492-501 (2001); Gusella et al., Nat. Rev. Neurosci. 1:109-15 (2000)), but these suggestions remain to be confirmed. Further, the lack of tractable genetic models has impeded the identification of additional genes involved in or associated with neurotoxicity.